EP3982960B1 - Treatments of hereditary angioedema - Google Patents

Treatments of hereditary angioedema Download PDF

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Publication number
EP3982960B1
EP3982960B1 EP20734283.3A EP20734283A EP3982960B1 EP 3982960 B1 EP3982960 B1 EP 3982960B1 EP 20734283 A EP20734283 A EP 20734283A EP 3982960 B1 EP3982960 B1 EP 3982960B1
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EP
European Patent Office
Prior art keywords
compound
formula
solvate
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP20734283.3A
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German (de)
English (en)
French (fr)
Other versions
EP3982960A1 (en
Inventor
Edward Paul FEENER
Sally Louise MARSH
Andreas MAETZEL
Michael David Smith
Christopher Martyn Yea
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Kalvista Pharmaceuticals Ltd
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Kalvista Pharmaceuticals Ltd
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Publication date
Application filed by Kalvista Pharmaceuticals Ltd filed Critical Kalvista Pharmaceuticals Ltd
Priority to HRP20230696TT priority Critical patent/HRP20230696T1/hr
Priority to EP23181261.1A priority patent/EP4282474A3/en
Priority to RS20230620A priority patent/RS64412B1/sr
Priority to SI202030247T priority patent/SI3982960T1/sl
Priority to SM20230261T priority patent/SMT202300261T1/it
Publication of EP3982960A1 publication Critical patent/EP3982960A1/en
Application granted granted Critical
Publication of EP3982960B1 publication Critical patent/EP3982960B1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the second dosage amount can be administered between about 4 and about 12 hours of the first (more specifically, between about 4 and about 8 hours, or at about 6 hours, following the first dosage amount), and the third dosage amount can be administered between about 4 and about 12 hours of the second (more specifically, between about 4 and about 8 hours, or at about 6 hours, following the second dosage amount). Even more specifically, the second dosage amount can be administered about 2 hours following the first dosage amount and the third dosage amount can be administered about 4 hours following the first dosage amount. In some embodiments, the second and third dosage amounts can both be administered within about 8 hours of the first. More specifically, the second dosage amount can be administered between about 3 and 5 hours of the first dosage amount and the third dosage amount can be administered between about 7 and about 8 hours following the first dosage amount.
  • the on-demand treatment can comprise administering four dosage amounts of the compound of Formula A within a 24 hour period starting from the time of taking the first dosage amount.
  • the dosage amount can be evenly spaced apart such that there is an approximately equal time period between each dosage amount e.g. taking the subsequent dosage amount at 8 hours, 16 hours and 24 hours following the initial dosage amount.
  • the second dosage amount can be administered between about 4 and about 12 hours of the first (more specifically, between about 4 and about 8 hours, or at about 6 hours, following the first dosage amount), and the third dosage amount can be administered between about 4 and about 12 hours of the second (more specifically, between about 4 and about 8 hours, or at about 6 hours, following the second dosage amount). Even more specifically, the second dosage amount can be administered about 2 hours following the first dosage amount and the third dosage amount can be administered about 4 hours following the first dosage amount. In some embodiments, the second and third dosage amounts can both be administered within about 8 hours of the first. More specifically, the second dosage amount can be administered between about 3 and 5 hours of the first dosage amount and the third dosage amount can be administered between about 7 and about 8 hours following the first dosage amount.
  • molecular ions were obtained using LCMS which was carried out using an Agilent Poroshell 120 EC-C18 (2.7 ⁇ m, 3.0 ⁇ 50mm) column with 0.1% v/v Formic acid in water [eluent A]; MeCN [eluent B]; Flow rate 0.8mL/min and 1.5 minutes equilibration time between samples, gradient shown below. Mass detection was afforded with API 2000 mass spectrometer (electrospray).
  • Plasma free fraction was determined using "Rapid Equilibrium Dialysis” system (Thermo Scientific), test compounds were prepared at 5 ⁇ M in neat human plasma and dialysed against phosphate buffer for 5 hrs at 37°C. Quantification of the compound partitioned in two chambers of the dialysis device was performed via LCMS/ MS. Fraction of compound unbound to plasma proteins presented as % of total.
  • the compound of Formula A appears to be a highly potent inhibitor of PKa with 17-fold and 20-fold potency vs. exogenously added C1-INH in diluted plasma ( Figure 2A ) and undiluted plasma ( Figure 2B ), respectively.
  • Table 1 showing the biochemical profile of the therapies tested in this example.
  • IC 50 purified enzyme nM IC 50 plasma enzyme nM K on ( ⁇ M -1 sec -1 ) Plasma Free Fraction % HK protection % C1-INH 50 1700 0.04
  • Figures 13A and 13B show the time course of dextran sulfate-activated cleavage of HK in HAE whole undiluted plasma determined using western blotting, and a representative blot.
  • the study is a randomized, double-blind, placebo-controlled, phase 2, cross-over clinical trial evaluating the efficacy and safety of the compound of formula A ("the compound”), an oral plasma kallikrein inhibitor, in the on-demand treatment of angioedema attacks in adult subjects with hereditary angioedema type I or II (EudraCT number: 2018-004489-32).
  • the compound an oral plasma kallikrein inhibitor
  • the PK parameters of the compound will be determined from the individual concentration versus time data using Phoenix WinNonlin. In case of a deviation from the theoretical time, the actual time of blood sample will be used in the calculation of the derived PK parameters. Individual concentrations and derived PK parameters of the compound in plasma will be listed and summarized for each treatment. Individual and geometric mean concentration-time data will be plotted on linear and semi-logarithmic scales.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Pulmonology (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicinal Preparation (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
EP20734283.3A 2019-06-14 2020-06-15 Treatments of hereditary angioedema Active EP3982960B1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
HRP20230696TT HRP20230696T1 (hr) 2019-06-14 2020-06-15 Liječenje hereditarnog angioedema
EP23181261.1A EP4282474A3 (en) 2019-06-14 2020-06-15 Treatments of hereditary angioedema
RS20230620A RS64412B1 (sr) 2019-06-14 2020-06-15 Tretmani naslednog angioedema
SI202030247T SI3982960T1 (sl) 2019-06-14 2020-06-15 Zdravljenja hereditarnega angioedema
SM20230261T SMT202300261T1 (it) 2019-06-14 2020-06-15 Trattamenti dell’angioedema ereditario

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201962861725P 2019-06-14 2019-06-14
GBGB1910116.1A GB201910116D0 (en) 2019-07-15 2019-07-15 Treatments of hereditary angioedema
PCT/GB2020/051439 WO2020249977A1 (en) 2019-06-14 2020-06-15 Treatments of hereditary angioedema

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP23181261.1A Division EP4282474A3 (en) 2019-06-14 2020-06-15 Treatments of hereditary angioedema

Publications (2)

Publication Number Publication Date
EP3982960A1 EP3982960A1 (en) 2022-04-20
EP3982960B1 true EP3982960B1 (en) 2023-06-28

Family

ID=67700145

Family Applications (2)

Application Number Title Priority Date Filing Date
EP20734283.3A Active EP3982960B1 (en) 2019-06-14 2020-06-15 Treatments of hereditary angioedema
EP23181261.1A Pending EP4282474A3 (en) 2019-06-14 2020-06-15 Treatments of hereditary angioedema

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP23181261.1A Pending EP4282474A3 (en) 2019-06-14 2020-06-15 Treatments of hereditary angioedema

Country Status (34)

Country Link
US (1) US20220218680A1 (enExample)
EP (2) EP3982960B1 (enExample)
JP (3) JP7356518B2 (enExample)
KR (1) KR102748728B1 (enExample)
CN (1) CN114126612A (enExample)
AR (1) AR119158A1 (enExample)
AU (1) AU2020293614B2 (enExample)
BR (1) BR112021024664A2 (enExample)
CA (1) CA3142218A1 (enExample)
CL (2) CL2021003244A1 (enExample)
DK (1) DK3982960T3 (enExample)
EA (1) EA202193019A1 (enExample)
ES (1) ES2956471T3 (enExample)
FI (1) FI3982960T3 (enExample)
GB (1) GB201910116D0 (enExample)
HR (1) HRP20230696T1 (enExample)
HU (1) HUE063163T2 (enExample)
IL (1) IL288615A (enExample)
LT (1) LT3982960T (enExample)
MA (1) MA56187B1 (enExample)
MD (1) MD3982960T2 (enExample)
MX (1) MX2021014557A (enExample)
MY (1) MY205687A (enExample)
PH (1) PH12021552966A1 (enExample)
PL (1) PL3982960T3 (enExample)
PT (1) PT3982960T (enExample)
RS (1) RS64412B1 (enExample)
SG (1) SG11202113304YA (enExample)
SI (1) SI3982960T1 (enExample)
SM (1) SMT202300261T1 (enExample)
TW (1) TW202112370A (enExample)
UA (1) UA129869C2 (enExample)
WO (1) WO2020249977A1 (enExample)
ZA (1) ZA202110685B (enExample)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201609607D0 (en) 2016-06-01 2016-07-13 Kalvista Pharmaceuticals Ltd Polymorphs of N-(3-Fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1-({4-((2-oxopy ridin-1-yl)methyl)phenyl}methyl)pyrazole-4-carboxamide and salts
GB201719881D0 (en) 2017-11-29 2018-01-10 Kalvista Pharmaceuticals Ltd Solid forms of plasma kallikrein inhibitor and salts thereof
GB201910116D0 (en) * 2019-07-15 2019-08-28 Kalvista Pharmaceuticals Ltd Treatments of hereditary angioedema
EP4010333A1 (en) 2019-08-09 2022-06-15 Kalvista Pharmaceuticals Limited Plasma kallikrein inhibitors
WO2022084693A1 (en) * 2020-10-23 2022-04-28 Kalvista Pharmaceuticals Limited Treatments of angioedema
WO2022172006A1 (en) 2021-02-09 2022-08-18 Kalvista Pharmaceuticals Limited Treatments of hereditary angioedema
SI4288036T1 (sl) 2022-04-27 2024-10-30 Kalvista Pharmaceuticals Limited Formulacije zaviralca plazemskega kalikreina
CN116003386B (zh) * 2022-11-20 2024-03-26 药康众拓(北京)医药科技有限公司 一种氘代n-苄基吡啶酮吡唑甲酰胺类化合物、药物组合物和用途
WO2025172693A1 (en) 2024-02-13 2025-08-21 Kalvista Pharmaceuticals Limited Oral sebetralstat for the treatment of an attack of hereditary angioedema
WO2025172692A1 (en) 2024-02-13 2025-08-21 Kalvista Pharmaceuticals Limited Oral sebetralstat for the treatment of an attack of hereditary angioedema

Family Cites Families (20)

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US5187157A (en) 1987-06-05 1993-02-16 Du Pont Merck Pharmaceutical Company Peptide boronic acid inhibitors of trypsin-like proteases
GB9019558D0 (en) 1990-09-07 1990-10-24 Szelke Michael Enzyme inhibitors
SE9301911D0 (sv) 1993-06-03 1993-06-03 Ab Astra New peptide derivatives
US5589467A (en) 1993-09-17 1996-12-31 Novo Nordisk A/S 2,5',N6-trisubstituted adenosine derivatives
GB0205527D0 (en) 2002-03-08 2002-04-24 Ferring Bv Inhibitors
US7429604B2 (en) 2004-06-15 2008-09-30 Bristol Myers Squibb Company Six-membered heterocycles useful as serine protease inhibitors
CA2658523C (en) 2006-07-31 2012-06-12 Activesite Pharmaceuticals, Inc. Inhibitors of plasma kallikrein
DE102006050672A1 (de) 2006-10-24 2008-04-30 Curacyte Discovery Gmbh Hemmstoffe des Plasmins und des Plasmakallikreins
JP2013121919A (ja) 2010-03-25 2013-06-20 Astellas Pharma Inc 血漿カリクレイン阻害剤
WO2012004678A2 (en) 2010-07-07 2012-01-12 The Medicines Company (Leipzig) Gmbh Serine protease inhibitors
WO2012009009A2 (en) 2010-07-14 2012-01-19 Addex Pharma S.A. Novel 2-amino-4-pyrazolyl-thiazole derivatives and their use as allosteric modulators of metabotropic glutamate receptors
US9290485B2 (en) 2010-08-04 2016-03-22 Novartis Ag N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
GB2494851A (en) 2011-07-07 2013-03-27 Kalvista Pharmaceuticals Ltd Plasma kallikrein inhibitors
GB201300304D0 (en) 2013-01-08 2013-02-20 Kalvista Pharmaceuticals Ltd Benzylamine derivatives
PT3305778T (pt) 2013-05-23 2022-05-02 Kalvista Pharmaceuticals Ltd Inibidores de calicreína plasmática
EP2815749A1 (en) * 2013-06-20 2014-12-24 IP Gesellschaft für Management mbH Solid form of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione having specified X-ray diffraction pattern
EP2886107A1 (en) * 2013-12-17 2015-06-24 ObsEva S.A. Oral formulations of pyrrolydine derivatives
GB201421083D0 (en) 2014-11-27 2015-01-14 Kalvista Pharmaceuticals Ltd Enzyme inhibitors
GB201721515D0 (en) * 2017-12-21 2018-02-07 Kalvista Pharmaceuticals Ltd Dosage forms comprising a plasma kallikrein inhibtor
GB201910116D0 (en) 2019-07-15 2019-08-28 Kalvista Pharmaceuticals Ltd Treatments of hereditary angioedema

Also Published As

Publication number Publication date
CL2023000639A1 (es) 2023-10-30
DK3982960T3 (da) 2023-08-21
US20220218680A1 (en) 2022-07-14
JP2025124716A (ja) 2025-08-26
LT3982960T (lt) 2023-08-25
JP7688078B2 (ja) 2025-06-03
ES2956471T3 (es) 2023-12-21
AU2020293614A1 (en) 2022-01-27
BR112021024664A2 (pt) 2022-05-31
EP4282474A2 (en) 2023-11-29
EP3982960A1 (en) 2022-04-20
PL3982960T3 (pl) 2024-01-15
JP2023166406A (ja) 2023-11-21
PT3982960T (pt) 2023-09-26
EA202193019A1 (ru) 2022-03-24
SMT202300261T1 (it) 2023-09-06
MA56187A (fr) 2022-04-20
RS64412B1 (sr) 2023-09-29
IL288615A (en) 2022-02-01
SI3982960T1 (sl) 2023-10-30
CL2021003244A1 (es) 2022-09-30
FI3982960T3 (fi) 2023-08-29
JP7356518B2 (ja) 2023-10-04
AU2020293614B2 (en) 2024-08-15
MY205687A (en) 2024-11-06
MD3982960T2 (ro) 2023-12-31
EP4282474A3 (en) 2024-02-14
CA3142218A1 (en) 2020-12-17
CN114126612A (zh) 2022-03-01
MX2021014557A (es) 2022-01-11
ZA202110685B (en) 2024-06-26
KR102748728B1 (ko) 2024-12-30
SG11202113304YA (en) 2021-12-30
KR20220024220A (ko) 2022-03-03
TW202112370A (zh) 2021-04-01
UA129869C2 (uk) 2025-08-27
GB201910116D0 (en) 2019-08-28
PH12021552966A1 (en) 2022-07-25
MA56187B1 (fr) 2023-09-27
NZ782935A (en) 2025-02-28
JP2022536287A (ja) 2022-08-15
AR119158A1 (es) 2021-12-01
HRP20230696T1 (hr) 2023-10-13
WO2020249977A1 (en) 2020-12-17
HUE063163T2 (hu) 2023-12-28

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